Methods of treating HIV infection

ABSTRACT

The invention encompasses pharmaceutical compositions and methods for using Compound 1 in combination with other agents for treating patients with AIDS or HIV infection.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional application U.S.Ser. No. 60/555,767, filed Mar. 24, 2004.

BACKGROUND OF THE INVENTION

HIV-1 (human immunodeficiency virus-1) infection remains a major medicalproblem, with an estimated 42 million people infected worldwide at theend of 2002. The number of cases of HIV and AIDS (acquiredimmunodeficiency syndrome) has risen rapidly. In 2002, approximately 5million new infections were reported and 3.1 million people died fromAIDS. Currently available drugs for the treatment of HIV include tennucleoside reverse transcriptase (RT) inhibitors or approved single pillcombinations: zidovudine or AZT (or Retrovir®), didanosine or DDI (orVidex®), stavudine or D4T (or Zerit®), lamivudine or 3TC (or Epivir®),zalcitabine or DDC (or Hivid®), abacavir succinate (or Ziagen®),tenofovir disoproxil fumarate salt (or Vireade), emtricitabine (orEmtriva®), Combivir® (contains 3TC and AZT), Trizivir® (containsabacavir, 3TC and AZT); three non-nucleoside reverse transcriptaseinhibitors: nevirapine (or Viramune®), delavirdine (or Rescriptor®) andefavirenz (or Sustiva®), eight peptidomimetic protease inhibitors orapproved formulations: saquinavir (or Invirase® or Fortovase®),indinavir (or Crixivan®), ritonavir (or Norvir®), nelfinavir (orViracept®), amprenavir (or Agenerase®), atazanavir (Reyataz®),fosamprenavir (or Lexiva), Kaletra® (contains lopinavir and ritonavir),and one fusion inhibitor enfuvirtide (or T-20 or Fuzeon®).

Each of these drugs can only transiently restrain viral replication ifused alone. However, when used in combination, these drugs have aprofound effect on viremia and disease progression. In fact, significantreductions in death rates among AIDS patients have been recentlydocumented as a consequence of the widespread application of combinationtherapy. Despite these impressive results, 30 to 50% of patientsultimately fail combination drug therapies. Insufficient drug potency,non-compliance, restricted tissue penetration and drug-specificlimitations within certain cell types (e.g. most nucleoside analogscannot be phosphorylated in resting cells) may account for theincomplete suppression of sensitive viruses. Furthermore, the highreplication rate and rapid turnover of HIV-1 combined with the frequentincorporation of mutations, leads to the appearance of drug-resistantvariants and treatment failures when sub-optimal drug concentrations arepresent (Larder and Kemp; Gulick; Kuritzkes; Morris-Jones et al;Schinazi et al; Vacca and Condra; Flexner; Berkhout and Ren et al; (Ref.6-14)). Thus, there is continuing need for new compounds and methods oftreatment for HIV infection.

1-Benzoyl-4-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-piperazine(Compound 1) is an HIV-1 attachment inhibitor demonstrating potentantiviral activity against a variety of laboratory and clinical strainsof HIV-1 (see U.S. patent application U.S. 2003 0207910, published Nov.6, 2003).

Compound 1 acts by selectively preventing attachment of the exteriorviral envelope protein gp120 to its cellular receptor CD4. Binding ofgp120 to CD4 is the first step in viral entry and is distinct from thesubsequent interaction with a chemokine receptor (CCR5 or CXCR4) orvirus-cell fusion event. By inhibiting this interaction, Compound 1blocks viral entrance into cells.

DESCRIPTION OF THE INVENTION

The invention encompasses pharmaceutical compositions and methods fortreating HIV infection and AIDS.

One aspect of the invention is a method for treating HIV infection in ahuman patient comprising the administration of a therapeuticallyeffective amount of1-benzoyl-4-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-piperazine(Compound 1), or a pharmaceutically acceptable salt or solvate thereof,with a therapeutically effective amount of at least one other agent usedfor treatment of AIDS or HIV infection selected from the groupconsisting of nucleoside HIV reverse transcriptase inhibitors,non-nucleoside HIV reverse transcriptase inhibitors, HIV proteaseinhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, andHIV integrase inhibitors.

Another aspect of the invention is a method wherein the agent is anucleoside HIV reverse transcriptase inhibitor.

Another aspect of the invention is a method wherein the nucleoside HIVreverse transcriptase inhibitor is selected from the group consisting ofabacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir,zalcitabine, and zidovudine, or a pharmaceutically acceptable salt orsolvate thereof.

Another aspect of the invention is a method wherein the agent is anon-nucleoside HIV reverse transcriptase inhibitor.

Another aspect of the invention is a method wherein the non-nucleosideHIV reverse transcriptase inhibitor is selected from the groupconsisting of delavirdine, efavirenz, and nevirapine, or apharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a method wherein the agent is an HIVprotease inhibitor.

Another aspect of the invention is a method wherein the HIV proteaseinhibitor is selected from the group consisting of amprenavir,atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir andfosamprenavir, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a method wherein the agent is an HIVfusion inhibitor.

Another aspect of the invention is a method wherein the HIV fusioninhibitor is enfuvirtide or T-1249, or a pharmaceutically acceptablesalt or solvate thereof.

Another aspect of the invention is a method wherein the agent is an HIVattachment inhibitor.

Another aspect of the invention is a method wherein the agent is a CCR5inhibitor.

Another aspect of the invention is a method wherein the CCR5 inhibitoris selected from the group consisting of Sch-C, Sch-D, TAK-220, PRO-140,and UK-427,857, or a pharmaceutically acceptable salt or solvatethereof.

Another aspect of the invention is a method wherein the agent is a CXCR4inhibitor.

Another aspect of the invention is a method wherein the CXCR4 inhibitoris AMD-3100, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a method wherein the agent is an HIVbudding or maturation inhibitor.

Another aspect of the invention is a method wherein the budding ormaturation inhibitor is PA-457, or a pharmaceutically acceptable salt orsolvate thereof.

Another aspect of the invention is a method wherein the agent is an HIVintegrase inhibitor.

Another aspect of the invention is a method wherein the HIV integraseinhibitor is 3-[(4-fluorobenzyl)methoxycarbamoyl]-2-hydroxyacrylic acidor2-(2,2)-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(4-fluorobenzyl)-N-methoxyacetamide,or a salt or solvate thereof.

Another aspect of the invention is a pharmaceutical compositioncomprising a therapeutically effective amount of1-benzoyl-4-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-piperazine,or a pharmaceutically acceptable salt or solvate thereof, with at leastone other agent used for treatment of AIDS or HIV infection selectedfrom the group consisting of nucleoside HIV reverse transcriptaseinhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIVprotease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors,CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors,and HIV integrase inhibitors, and a pharmaceutically acceptable carrier.

Another aspect of the invention is the composition wherein the agent isa nucleoside HIV reverse transcriptase inhibitor.

Another aspect of the invention is the composition wherein thenucleoside HIV transcriptase inhibitor is selected from the groupconsisting of abacavir, didanosine, emtricitabine, lamivudine,stavudine, tenofovir, zalcitabine, and zidovudine, or a pharmaceuticallyacceptable salt or solvate thereof.

Another aspect of the invention is the composition wherein the agent isa non-nucleoside HIV reverse transcriptase inhibitor.

Another aspect of the invention is the composition wherein thenon-nucleoside HIV reverse transcriptase inhibitor is selected from thegroup consisting of delavirdine, efavirenz, and nevirapine, or apharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is the composition wherein the agent isan HIV protease inhibitor.

Another aspect of the invention is the composition wherein the HIVprotease inhibitor is selected from the group consisting of amprenavir,atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir andfosamprenavir, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is the composition wherein the agent isan HIV fusion inhibitor.

Another aspect of the invention is the composition method wherein theHIV fusion inhibitor is enfuvirtide or T-1249, or a pharmaceuticallyacceptable salt or solvate thereof.

Another aspect of the invention is the composition wherein the agent isan HIV attachment inhibitor.

Another aspect of the invention is the composition wherein the agent isa CCR5 inhibitor.

Another aspect of the invention is the composition wherein the CCR5inhibitor is selected from the group consisting of Sch-C, Sch-D,TAK-220, PRO-140, and UK-427,857, or a pharmaceutically acceptable saltor solvate thereof.

Another aspect of the invention is a method wherein the agent is a CXCR4inhibitor.

Another aspect of the invention is a method wherein the CXCR4 inhibitoris AMD-3100, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is the composition wherein the agent isan HIV budding or maturation inhibitor.

Another aspect of the invention is the composition wherein the buddingor maturation inhibitor is PA-457, or a pharmaceutically acceptable saltor solvate thereof.

Another aspect of the invention is the composition wherein the agent isan HIV integrase inhibitor.

Another aspect of the invention is the composition wherein the HIVintegrase inhibitor is3-[(4-fluorobenzyl)methoxycarbamoyl]-2-hydroxyacrylic acid or2-(2,2)-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(4-fluorobenzyl)-N-methoxyacetamide,or a pharmaceutically acceptable salt or solvate thereof.

“Combination,” “coadministration,” “concurrent,” and similar termsreferring to the administration of Compound 1 with at least one anti-HIVagent mean that the components are part of a combination antiretroviraltherapy or highly active antiretroviral therapy (HAART) as understood bypractitioners in the field of AIDS and HIV infection.

“Therapeutically effective” means the amount of agent required toprovide a meaningful patient benefit as understood by practitioners inthe field of AIDS and HIV infection. In general, the goals of treatmentare suppression of viral load, restoration and preservation ofimmunologic function, improved quality of life, and reduction ofHIV-related morbidity and mortality.

“Patient” means a person infected with the HIV virus and suitable fortherapy as understood by practitioners in the field of AIDS and HIVinfection.

“Treatment,” “therapy,” “regimen,” “HIV infection,” “ARC,” “AIDS” andrelated terms are used as understood by practitioners in the field ofAIDS and HIV infection.

The invention includes all pharmaceutically acceptable salt forms ofCompound 1. Pharmaceutically acceptable salts are those in which thecounter ions do not contribute significantly to the physiologicalactivity or toxicity of the compounds and as such function aspharmacological equivalents. In many instances, salts have physicalproperties that make them desirable for formulation, such as solubilityor crystallinity. The salts can be made according to common organictechniques employing commercially available reagents. Suitable anionicsalt forms include acetate, acistrate, besylate, bromide, chloride,citrate, fumarate, glucouronate, hydrobromide, hydrochloride,hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate,phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate.

The invention also includes all solvated forms of Compound 1,particularly hydrates. Solvates do not contribute significantly to thephysiological activity or toxicity of the compounds and as such functionas pharmacological equivalents. Solvates may form in stoichiometricamounts or may form from adventitious solvent or a combination of both.One type of solvate is hydrate. Some hydrated forms include monohydrate,hemihydrate, and dihydrate.

Biological Methods

Compound 1 demonstrated synergistic or additive-synergistic HIVantiviral activity when used in conjunction with a variety of otherantiviral agents, as described below.

Virus and cell lines. The T-cell lines, MT-2 and PM-1 were obtainedthrough the AIDS Research and Reference Reagent Program, NIAID, and werecontributed by Dr. D. Richman and Dr. R. Gallo, respectively. Both celllines were cultured in RPMI 1640 medium supplemented with 10% fetalbovine serum, 2 mM L-glutamine and sub-cultured twice a week. The LAIstrain of HIV-1 was obtained from the Fred Hutchinson Cancer ResearchCenter, and the Bal strain was from NIH. Both virus stocks wereamplified and titered in MT-2 cells (LAI) and PM-1 cells (Bal) using avirus infectivity assay.

Chemicals. Compound 1, atazanavir, didanosine, stavudine, efavirenz,enfuvirtide (T-20), T-1249, AMD-3100, Sch-C, Sch-D and UK-427,857 weresynthesized using published or known reactions. Amprenavir, indinavir,nelfinavir, nevirapine, lopinavir, lamivudine, ritonavir, tenofovir,saquinavir, delavirdine and abacavir were extracted from commercialformulations of the prescribed drugs and purified using published orcommon techniques. Tenofovir was tested as tenovir disopoxil fumerate.Zalcitabine was obtained from the National Institutes of Health.Zidovudine was purchased from Sigma and emtricitabine from MoravekBiochemicals. 3-[(4-Fluorobenzyl)methoxycarbamoyl]-2-hydroxyacrylic acid(Compound 2) and2-(2,2)-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(4-fluorobenzyl)-N-methoxyacetamide(Compound 3) are described in U.S. Pat. No. 6,777,440. Purities of theanti-HIV agents were greater than 95% except for AMD-3100 (>90%), Sch-D(80%), and UK-427,857 (>90%).

Drug Susceptibility and Cytotoxicity Assays. For drug susceptibilityassays, MT-2 cells were infected with HIV-1 LAI (or PM-1 cells withHIV-1 Bal) at an MOI of 0.005, and seeded into 96-well microtiter plates(0.1×10⁶ cells/ml) containing serial dilutions of test compounds. Thedrug combinations were set up using ratios of the two drugs of 1:1,1:2.5 and 2.5:1 times the EC₅₀ value determined for each drug in priormultiple experiments. Each drug ratio consisted of an array of 3-foldserial dilutions, and was performed in quadruplicate. The plates wereincubated at 37° C./5% CO₂. The MT-2 cells infected with HIV-1 LAI wereincubated for 5 days. On day-five post-infection, 20 μl from each wellwas harvested and quantitated by a reverse transcriptase (RT) assay, orin samples involving non-nucleoside RT inhibitors, an MTS assay. ThePM-1 cells infected with HIV-1 Bal and used for studying thecombinations with CCR5 inhibitors were incubated for six days. Onday-six post-infection, 20 μl from each well was harvested, 20- and50-fold diluted and quantitated by p24 assay. Cytotoxicity assays wereperformed using uninfected cells, exposed to the same drug combinations,and incubated for six days. Cell viability was determined by an MTSassay. The CC₅₀ values were calculated by using the exponential form ofthe median effect equation as mentioned below for calculation of EC₅₀.

Analysis of Drug Combination Effects. For determination of CI values,drugs were diluted in a fixed ratio and multiple ratios were analyzed.The drug serial dilutions spanned a range of concentrations near theEC₅₀ value of each compound, so that equivalent antiviral activitiescould be compared. Concentration-response curves were estimated for eachindividual drug and every combination using the median-effect equation.The equation was fit using a nonlinear regression routine (Proc Nlin) inPC SAS version 8.01 (SAS Institute Inc., SAS Version 8.01, Cary, N.C.:SAS Institute Inc., 1990).

EC₅₀ values for each drug were determined from the single drugexperiments, using the median effect equation, Fa=1I/[1+(ED₅₀/drugconcentration)^(m)]. In this equation, Fa stands for “fractionaffected,” and represents the fraction of the viral load that has beeninactivated. For example, Fa of 0.75 indicates that viral replicationhad been inhibited by 75%, relative to the no-drug controls. ED₅₀ isdrug concentration that is expected to reduce the amount of virus by50%, and m is a parameter that reflects the slope of theconcentration-response curve.

To assess antiviral effects of different drug combination treatments,combination indices (CIs) were calculated according to Chou and Rideout.The combination index was computed asCI=[D] _(1/[Dm]1+) [D] _(2/[Dm]2)

In this equation [Dm] 1 and [Dm]2 are the concentrations of drugs thatwould individually produce a specific level of effect, while [D] 1 and[D]2 are the concentrations of drugs in combination that would producethe same level of effect.

Theoretically, additivity is implied if the CI is equal to one, synergyif the CI is less than one, and antagonism if the CI is greater thanone. However, extensive experience with combination studies indicatesthat there are inherent laboratory variables that must be taken intoaccount in interpreting the CIs. At best, we can construct a range thatcontains the likely values for the CI, given the noise in the data. Inthis report, these ranges are reported in parentheses next to each pointestimate of the CI. For example, when we report a CI of “0.53 (0.46,0.60)” this means that our best estimate of the CI is 0.53, but due tonoise in the data, values from 0.46 to 0.60 are also reasonable valuesfor the CI. This range, 0.46 to 0.60 falls entirely below the value of1.0, and hence all likely values for the CI are less than 1.0.Therefore, we can infer synergistic behavior for this case. If the rangefell entirely above 1.0, we would infer antagonistic behavior. If therange were to include 1.0, we would infer additivity.

In carrying out the combination experiments below, the EC₅₀ for Compound1 and each comparator compound was determined during the course of eachstudy, and used in the subsequent data analysis. The determined valuesare consistent with our previously published data and are shown inTable 1. TABLE 1 Anti-HIV Activity of the Compounds Used in Two-DrugCombination Studies. Highest Concentration Compound EC₅₀ (μM) Used (μM)Compound 1 0.0001-0.0003 0.15 Abacavir 0.326 90 Tenofovir 0.008 6.0Zalcitabine 0.034 15 Didanosine 0.652 300 Stavudine 0.072 90 Zidovudine0.001 0.9 Lamivudine 0.030 12 Emtricitabine 0.025 30 Efavirenz 0.0010.15 Nevirapine 0.107 9.0 Delavirdine 0.025 0.5 Indinavir 0.003 3.0Atazanavir 0.0007 0.15 Lopinavir 0.004 3.0 Nelfinavir 0.003 0.9Amprenavir 0.011 3.0 Saquinavir 0.005 3.0 Ritonavir 0.007 3.0Enfuvirtide 0.001 0.9 T-1249 AMD-3100 0.005 0.8 SchC 0.0009 0.9 SchDUK-427,857 Compound 2 0.079 4.0

Two-Drug Combinations of Compound 1 with Nucleoside ReverseTranscriptase Inhibitors. Nucleoside RT inhibitors were combined withCompound 1 at a range of concentrations near the EC₅₀ value of eachcompound, so that equivalent antiviral activities could be compared. Allestimates were computed using SAS Proc NLIN, and a two-parameterlogistic. Data is presented in Table 2 as the combination indices andthe asymptotic confidence intervals for RT inhibitors at different molarratios (see Materials and Methods). Nucleoside RT inhibitors showsynergistic to additive-synergistic antiviral effects in combinationwith Compound 1. No significant antagonism of anti-HIV activity isobserved. No enhanced cytotoxicity was encountered at the highestconcentrations tested with any of the drug combinations, as measured byMTS reduction assay. TABLE 2 Two-Drug Combinations using Compound 1 andNucleoside Reverse Transcriptase Inhibitors. Combination Indices at %HIV Inhibition^(b) Molar Ratio (Confidence Interval) Overall (EC₅₀Ratio)^(a) 50% 75% 90% Result Zalcitabine 1:100 (1:1) 0.58 (0.46, 0.69)0.61 (0.43, 0.78) 0.69 (0.39, 1.00) Synergistic 1:250 (1:2.5) 0.55(0.47, 0.63) 0.56 (0.44, 0.68) 0.65 (0.43, 0.86) 1:40 (2.5:1) 0.24(0.22, 0.26) 0.18 (0.16, 0.20) 0.14 (0.12, 0.17) Emtricitabine 1:200(1:1) 0.42 (0.35, 0.50) 0.49 (0.37, 0.61) 0.60 (0.38, 0.83) Synergistic1:500 (1:2.5) 0.19 (0.15, 0.22) 0.35 (0.26, 0.44) 0.67 (0.36, 0.99) 1:80(2.5:1) 0.11 (0.09, 0.12) 0.26 (0.21, 0.31) 0.67 (0.44, 0.89) Didanosine1:2000 (1:1) 0.31 (0.29, 0.32) 0.16 (0.15, 0.17) 0.08 (0.08, 0.09)Synergistic 1:5000 (1:2.5) 0.27 (0.23, 0.31) 0.31 (0.24, 0.38) 0.35(0.23, 0.48) 1:800 (2.5:1) 0.15 (0.11, 0.19) 0.31 (0.22, 0.40) 0.65(0.31, 0.98) Tenofovir 1:40 (1:1) 0.09 (0.07, 0.11) 0.17 (0.12, 0.22)0.34 (0.18, 0.49) Moderate- 1:100 (1:2.5) 0.18 (0.13, 0.22) 0.37 (0.23,0.50) 0.79 (0.30, 1.28) Synergistic 1:16 (2.5:1) 0.37 (0.31, 0.44) 0.60(0.46, 0.73) 0.97 (0.62, 1.33) Stavudine 1:600 (1:1) 0.52 (0.40, 0.64)0.60 (0.41, 0.80) 0.75 (0.36, 1.14) Moderate- 1:1500 (1:2.5) 0.38 (0.31,0.45) 0.37 (0.28, 0.46) 0.40 (0.23, 0.56) Synergistic 1:240 (2.5:1) 0.69(0.51, 0.88) 0.78 (0.49, 1.07) 0.92 (0.36, 1.48) Zidovudine 1:6 (1:1)0.25 (0.17, 0.34) 0.53 (0.29, 0.78) 1.13 (0.24, 2.02) Additive- 1:15(1:2.5) 0.46 (0.36, 0.56) 0.52 (0.36, 0.68) 0.59 (0.29, 0.89)Synergistic 1:2.4 (2.5:1) 0.37 (0.28, 0.47) 0.49 (0.32, 0.67) 0.66(0.28, 1.05) Lamivudine 1:80 (1:1) 0.75 (0.45, 1.05) 0.79 (0.35, 1.23)0.90 (0.11, 1.69) Additive- 1:200 (1:2.5) 0.13 (0.10, 0.16) 0.21 (0.16,0.27) 0.39 (0.21, 0.58) Synergistic 1:32 (2.5:1) 0.14 (0.10, 0.17) 0.26(0.18, 0.33) 0.49 (0.22, 0.75) Abacavir 1:1000 (1:1) 0.69 (0.49, 0.89)0.77 (0.46, 1.09) 0.87 (0.30, 1.44) Additive- 1:2500 (1:2.5) 0.56 (0.45,0.67) 0.51 (0.37, 0.65) 0.48 (0.27, 0.68) Synergistic 1:400 (2.5:1) 0.10(0.05, 0.14) 0.27 (0.16, 0.39) 0.76 (0.14, 1.37)^(a)Ratio of Compound 1 to comparator compound.^(b)A lower bound of the asymptotic confidence interval greater than 1indicates antagonisms, an upper bound of less than 1 indicatessynergism, and a value of 1 being contained in the interval indicatesadditivity. The 95% confidence intervals are shown in parenthesis, andrepresent a measure of variability in the data.

Two-Drug Combinations of Compound 1 with Non-Nucleoside ReverseTranscriptase Inhibitors. The results presented in Table 3 show that thecombined effect of Compound 1 with efavirenz and delavirdine issynergistic while the effect with nevapiradine is additive-synergystic.No enhanced cytotoxicity was observed at the highest concentrationstested with any of the drug combinations. TABLE 3 Two-Drug Combinationsusing Compound 1 and Non-Nucleoside Reverse Transcriptase Inhibitors.Combination Indices at % HIV Inhibition^(b) Molar Ratio (ConfidenceInterval) Overall (EC₅₀ Ratio)^(a) 50% 75% 90% Result Efavirenz 1:2.5(1:1) 0.70 (0.50, 0.89) 0.47 (0.30, 0.64) 0.32 (0.13, 0.50) Synergistic1:6.25 (1:2.5) 0.47 (0.28, 0.65) 0.46 (0.21, 0.70) 0.45 (0.06, 0.83) 1:1(2.5:1) 0.52 (0.36, 0.69) 0.39 (0.21, 0.57) 0.30 (0.08, 0.51)Delavirdine 1:8.33 (1:1) 0.90 (0.75, 1.06) 0.49 (0.38, 0.61) 0.28 (0.18,0.39) Synergistic 1:20.8 (1:2.5) 0.57 (0.42, 0.71) 0.55 (0.36, 0.75)0.57 (0.26, 0.89) 1:3.33 (2.5:1) 0.64 (0.49, 0.78) 0.46 (0.31, 0.60)0.34 (0.17, 0.50) Nevirapine 1:150 (1:1) 0.19 (0.15, 0.23) 0.22 (0.16,6.28) 0.26 (0.15, 0.38) Additive- 1:375 (1:2.5) 0.48 (0.35, 0.62) 0.66(0.40, 0.92) 0.92 (0.35, 1.49) Synergistic 1:60 (2.5:1) 0.58 (0.48,0.67) 0.99 (0.76, 1.22) 1.71 (1.09, 2.33)^(a)Ratio of Compound 1 to comparator compound.^(b)A lower bound of the asymptotic confidence interval greater than 1indicates antagonisms, an upper bound of less than 1 indicatessynergism, and a value of 1 being contained in the interval indicatesadditivity. The 95% confidence intervals are shown in parenthesis, andrepresent a measure of variability in the data.

Two-Drug Combinations Involving Compound 1 and HIV Protease Inhibitors.In general, protease combinations with Compound 1 are synergistic toadditive-synergistic. No cytotoxicity was observed at the highestconcentrations used in any of these combination antiviral assays.Results from this two-drug combination study are summarized in Table 4.TABLE 4 Two-Drug Combination using Compound 1 and Protease Inhibitors.Combination Indices at % HIV Inhibition^(b) Molar Ratio (ConfidenceInterval) Overall (EC₅₀ Ratio)^(a) 50% 75% 90% Result Ritonavir 1:33.3(1:1) 0.60 (0.49, 0.72) 0.61 (0.45, 0.77) 0.70 (0.41, 0.99) Synergistic1:83.3 (1:2.5) 0.54 (0.45, 0.63) 0.58 (0.44, 0.71) 0.73 (0.46, 1.00)1:13.3 (2.5:1) 0.23 (0.20, 0.26) 0.20 (0.17, 0.24) 0.19 (0.14, 0.24)Saquinavir 1:33.3 (1:1) 0.31 (0.28, 0.33) 0.31 (0.28, 0.35) 0.32 (0.26,0.38) Synergistic 1:83.3 (1:2.5) 0.60 (0.52, 0.67) 0.67 (0.56, 0.79)0.77 (0.56, 0.97) 1:13.3 (2.5:1) 0.39 (0.33, 0.45) 0.59 (0.46, 0.72)0.90 (0.58, 1.22) Atazanavir 1:1 (1:1) 0.53 (0.46, 0.60) 0.67 (0.54,0.79) 0.90 (0.64, 1.17) Additive- 1:2.5 (1:2.5) 0.23 (0.16, 0.30) 0.49(0.29, 0.69) 1.17 (0.38, 1.95) Synergistic 1:0.4 (2.5:1) 0.34 (0.26,0.42) 0.56 (0.38, 0.74) 0.97 (0.46, 1.48) Lopinavir 1:20 (1:1) 0.47(0.38, 0.56) 0.66 (0.48, 0.84) 1.02 (0.58, 1.46) Additive- 1:50 (1:2.5)0.89 (0.73, 1.05) 0.90 (0.67, 1.13) 1.00 (0.60, 1.40) Synergistic 1:8(2.5:1) 0.29 (0.25, 0.33) 0.37 (0.30, 0.44) 0.51 (0.37, 0.65) Nelfinavir1:6 (1:1) 0.39 (0.34, 0.44) 0.47 (0.39, 0.56) 0.58 (0.41, 0.74)Additive- 1:15 (1:2.5) 0.41 (0.32, 0.50) 0.81 (0.57, 1.05) 1.61 (0.84,2.37) Synergistic 1:2.4 (2.5:1) 0.12 (0.09, 0.15) 0.32 (0.22, 0.42) 0.87(0.38, 1.35) Amprenavir 1:33.3 (1:1) 0.14 (0.11, 0.17) 0.35 (0.26, 0.45)0.87 (0.46, 1.28) Additive- 1:83.3 (1:2.5) 0.13 (0.09, 0.17) 0.27 (0.17,0.38) 0.58 (0.19, 0.97) Synergistic 1:13.3 (2.5:1) 0.46 (0.32, 0.60)0.79 (0.46, 1.11) 1.33 (0.42, 2.25) Indinavir 1:20 (1:1) 0.41 (0.26,0.56) 0.69 (0.34, 1.04) 1.59 (0.29, 2.90) Additive- 1:50 (1:2.5) 0.30(0.18, 0.41) 0.62 (0.32, 0.92) 1.96 (0.29, 3.64) Synergistic 1:8 (2.5:1)0.05 (0.03, 0.06) 0.16 (0.13, 0.20) 0.68 (0.39, 0.98)^(a)Ratio of Compound 1 to comparator compound.^(b)A lower bound of the asymptotic confidence interval greater than 1indicates antagonisms, an upper bound of less than 1 indicatessynergism, and a value of 1 being contained in the interval indicatesadditivity. The 95% confidence intervals are shown in parenthesis, andrepresent a measure of variability in the data.

Two-Drug Combination of Compound 1 with Entry Inhibitors. The resultspresented in Table 5 indicate that the combination of Compound 1 withAMD-3100 is strongly synergistic at the 50 and 75% inhibition levels,with tendency to additivity at 90%. Therefore, it is classified asmoderate synergistic. No significant cytotoxicity was observed at thehighest concentration of the combined drugs. TABLE 5 Anti-HIV Activityfrom a Two-Drug Combination using Compound 1 and Entry InhibitorsCombination Indices at % HIV Inhibition^(b) Molar Ratio (ConfidenceInterval) Overall (EC₅₀ Ratio)^(a) 50% 75% 90% Result Enfuvirtide 1:10(1:1) 0.47 (0.40, 0.54) 0.53 (0.42, 0.65) 0.60 (0.39, 0.81) Synergistic1:25 (1:2.5) 0.48 (0.37, 0.60) 0.60 (0.40, 0.80) 0.75 (0.35, 1.15) 1:4(2.5:1) 0.35 (0.29, 0.40) 0.47 (0.37, 0.57) 0.63 (0.40, 0.86) T-1249AMD-3100 1:16 (1:1) 0.44 (0.29, 0.60) 0.62 (0.31, 0.92) 0.98 (0.21,1.76) Moderate- 1:40 (1:2.5) 0.56 (0.42, 0.70) 0.54 (0.35, 0.73) 0.66(0.29, 1.02) Synergistic 1:6.4 (2.5:1) 0.52 (0.36, 0.68) 0.61 (0.35,0.88) 0.77 (0.24, 1.31) SchC 1:10 (1:1) 0.19 (0.14, 0.25) 0.46 (0.29,0.63) 1.12 (0.4, 1.83) Additive- 1:25 (1:2.5) 0.50 (0.38, 0.61) 0.92(0.64, 1.21) 1.74 (0.83, 2.65) Synergistic 1:4 (2.5:1) 0.08 (0.05, 0.11)0.21 (0.14, 0.28) 0.54 (0.21, 0.88) SchD UK-427,857^(a)Ratio of Compound 1 to comparator compound.^(b)A lower bound of the asymptotic confidence interval greater than 1indicates antagonisms, an upper bound of less than 1 indicatessynergism, and a value of 1 being contained in the interval indicatesadditivity. The 95% confidence intervals are shown in parenthesis, andrepresent a measure of variability in the data.

Two-Drug Combination of Compound 1 with an HIV integrase inhibitor. Theresults presented in Table 6 indicate that the combination of Compound 1with Compound 2 is moderate synergistic. No significant cytotoxicity wasobserved at the highest concentration of the combined drugs. TABLE 6Anti-HIV Activity from a Two-Drug Combination using Compound 1 andCompound 2 Combination Indices at % HIV Inhibition^(b) Molar Ratio(Confidence Interval) Overall (EC₅₀ Ratio)^(a) 50% 75% 90% ResultBMS-538203 1:80 (1:1) 0.48 (0.39, 0.58) 0.51 (0.37, 0.65) 0.54 (0.31,0.76) Moderate- 1:200 (1:2.5) 0.44 (0.36, 0.53) 0.51 (0.37, 0.65) 0.59(0.34, 0.85) Synergistic 1:32 (2.5:1) 0.50 (0.36, 0.63) 0.70 (0.44,0.97) 1.00 (0.41, 1.59)^(a)Ratio of Compound 1 to comparator compound.^(b)A lower bound of the asymptotic confidence interval greater than 1indicates antagonisms, an upper bound of less than 1 indicatessynergism, and a value of 1 being contained in the interval indicatesadditivity. The 95% confidence intervals are shown in parenthesis, andrepresent a measure of variability in the data.

Pharmaceutical Composition and Methods of Use

Compound 1 inhibits HIV attachment, an essential step in HIVreplication, and can be useful for the treatment of HIV infection andthe consequent pathological conditions such as AIDS or ARC. As shownabove, Compound 1 is active in conjunction with a wide variety of otheragents and may be particularly beneficial in HAART and other newcombination compositions and therapies.

Compound 1 will generally be given as a pharmaceutical composition, andthe active ingredient of the composition may be comprised of Compound 1alone or Compound 1 and at least one other agent used for treating AIDSor HIV infection. The compositions will generally be made with apharmaceutically accepted carrier or vehicle, and may containconventional exipients. The compositions are made using commonformulation techniques. The invention encompasses all conventionalforms. Solid and liquid compositions are preferred. Some solid formsinclude powders, tablets, capsules, and lozenges. Tablets includechewable, buffered, and extended release. Capsules include entericcoated and extended release capsules. Powders are for both oral use andreconstitution into solution. Powders include lyophilized and flash-meltpowders. In a solid composition, Compound 1 and any antiretroviral agentare present in dosage unit ranges. Generally, Compound 1 will be in aunit dosage range of 1-1000 mg/unit. Some examples of dosages are 1 mg,10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg. Generally, otherantiretroviral agents will be present in a unit range similar to agentsof that class used clinically. Typically, this is 0.25-1000 mg/unit.

Liquids include aqueous solutions, syrups, elixers, emusions, andsuspensions. In a liquid composition, Compound 1 and any antiretroviralagent are present in dosage unit ranges. Generally, Compound 1 will bein a unit dosage range of 1-100 mg/mL. Some examples of dosages are 1mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL. Generally, otherantiretroviral agents will be present in a unit range similar to agentsof that class used clinically. Typically, this is 1-100 mg/mL.

The invention encompasses all conventional modes of administration; oraland parenteral (injected intramuscular, intravenous, subcutanaeous)methods are preferred. Generally, the dosing regimen will be similar toother antiretroviral agents used clinically. Typically, the daily dosewill be 1-100 mg/kg body weight daily for Compound 1. Generally, morecompound is required orally and less parenterally. The specific dosingregime, however, will be determined by a physician using sound medicaljudgement.

The invention also encompasses methods where Compound 1 is given incombination therapy. That is, Compound 1 can be used in conjunctionwith, but separately from, other agents useful in treating AIDS and HIVinfection. Some of these agents include HIV attachment inhibitors, CCR5inhibitors, CXCR4 inhibitors, HIV cell fusion inhibitors, HIV integraseinhibitors, HIV nucleoside reverse transcriptase inhibitors, HIVnon-nucleoside reverse transcriptase inhibitors, HIV proteaseinhibitors, budding and maturation inhibitors, immunomodulators, andanti-infectives. In these combination methods, Compound 1 will generallybe given in a daily dose of 1-100 mg/kg body weight daily in conjunctionwith other agents. The other agents generally will be given in theamounts used therapeutically. The specific dosing regime, however, willbe determined by a physician using sound medical judgement.

Table 7 lists some agents useful in treating AIDS and HIV infection,which are suitable for this invention. The invention, however, is notlimited to these agents. TABLE 7 DRUG NAME MANUFACTURER INDICATIONANTIVIRALS 097 Hoechst/Bayer HIV infection, AIDS, (non-nucleosidereverse ARC transcriptase inhibitor) Amprenavir Glaxo Wellcome HIVinfection, AIDS, 141 W94 ARC GW 141 (protease inhibitor) Abacavir(1592U89) Glaxo Wellcome HIV infection, AIDS, GW 1592 ARC (RT inhibitor)Acemannan Carrington Labs ARC (Irving, TX) Acyclovir Burroughs WellcomeHIV infection, AIDS, ARC, in combination with AZT AD-439 TanoxBiosystems HIV infection, AIDS, ARC AD-519 Tanox Biosystems HIVinfection, AIDS, ARC Adefovir dipivoxil Gilead Sciences HIV infection,ARC, AL-721 Ethigen PGL HIV positive, (Los Angeles, CA) AIDS AlphaInterferon Glaxo Wellcome Kaposi's sarcoma HIV in combination w/RetrovirAnsamycin Adria Laboratories ARC LM 427 (Dublin, OH) Erbamont (Stamford,CT) Antibody which Advanced Biotherapy AIDS, ARC Neutralizes pH ConceptsLabile alpha aberrant (Rockville, MD) Interferon AR177 Aronex Pharm HIVinfection, AIDS, ARC Beta-fluoro-ddA Nat'l Cancer InstituteAIDS-associated diseases BMS-232623 Bristol-Myers Squibb/ HIV infection,AIDS, (CGP-73547) Novartis ARC (protease inhibitor) BMS-234475Bristol-Myers Squibb/ HIV infection, AIDS, (CGP-61755) Novartis ARC(protease inhibitor) CI-1012 Warner-Lambert HIV-1 infection CidofovirGilead Science CMV retinitis, herpes, papillomavirus Curdlan sulfate AJIPharma USA HIV infection Cytomegalovirus MedImmune CMV retinitis Immuneglobin Cytovene Syntex Sight threatening Ganciclovir CMV peripheral, CMVretinitis Delaviridine Pharmacia-Upjohn HIV infection, AIDS, (RTinhibitor) ARC Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV Ind. Ltd.(Osaka, positive asymptomatic Japan) ddC Hoffman-La Roche HIV infection,AIDS, Dideoxycytidine ARC ddI Bristol-Myers Squibb HIV infection, AIDS,Dideoxyinosine ARC; combinationwith AZT/d4T DMP-450 AVID HIV infection,AIDS, (protease inhibitor) (Camden, NJ) ARC Efavirenz DuPont Merck HIVinfection, AIDS, (DMP 266) ARC (−)6-Chloro-4-(S)- cyclopropylethynyl-4(S)-trifluoro- methyl-1,4-dihydro- 2H-3,1-benzoxazin- 2-one, STOCRINE(non-nucleoside RT inhibitor) EL10 Elan Corp, PLC HIV infection(Gainesville, GA) Famciclovir Smith Kline herpes zoster, herpes simplexFTC (reverse transcriptase Emory University HIV infection, AIDS,inhibitor) ARC GS 840 Gilead HIV infection, AIDS, (reverse transcriptaseARC inhibitor) HBY097 Hoechst Marion HIV infection, AIDS,(non-nucleoside reverse Roussel ARC transcriptaseinhibitor) HypericinVIMRx Pharm. HIV infection, AIDS, ARC Recombinant Human TritonBiosciences AIDS, Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARCInterferon alfa-n3 Interferon Sciences ARC, AIDS Indinavir Merck HIVinfection, AIDS, ARC, asymptomatic HIV positive, also in combinationwith AZT/ddI/ddC ISIS 2922 ISIS Pharmaceuticals CMV retinitis KNI-272Nat'l Cancer Institute HIV-associated diseases Lamivudine, 3TC GlaxoWellcome HIV infection, AIDS, (reverse transcriptase ARC, also with AZTinhibitor) Lobucavir Bristol-Myers Squibb CMV infection NelfinavirAgouron HIV infection, AIDS, (protease inhibitor) Pharmaceuticals ARCNevirapine Boeheringer HIV infection, AIDS, (RT inhibitor) Ingleheim ARCNovapren Novaferon Labs, Inc. HIV inhibitor (Akron, OH) Peptide TPeninsula Labs AIDS Octapeptide (Belmont, CA) Sequence Trisodium AstraPharm. CMV retinitis, HIV Phosphonoformate Products, Inc. infection,other CMV infections PNU-140690 Pharmacia Upjohn HIV infection, AIDS,(protease inhibitor) ARC Probucol Vyrex HIV infection, AIDS RBC-CD4Sheffield Med. HIV infection, AIDS, Tech (Houston, TX) ARC RitonavirAbbott HIV infection, AIDS, (protease inhibitor) ARC SaquinavirHoffmann- HIV infection, AIDS, (protease inhibitor) LaRoche ARCStavudine; d4T Bristol-Myers Squibb HIV infection, AIDS, Didehydrodeoxy-ARC thymidine Valaciclovir Glaxo Wellcome Genital HSV & CMVinfectionsVirazole Viratek/ICN asymptomatic HIV- Ribavirin (Costa Mesa, CA)positive, LAS, ARC VX-478 Vertex HIV infection, AIDS, ARC ZalcitabineHoffmann-LaRoche HIV infection, AIDS, ARC, with AZT Zidovudine; AZTGlaxo Wellcome HIV infection, AIDS, ARC, Kaposi's sarcoma, incombination with other therapies Tenofovir disoproxil, Gilead HIVinfection, AIDS fumarate salt (Viread ®) (reverse transcriptaseinhibitor) Combivir ® GSK HIV infection, AIDS (reverse transcriptaseinhibitor) abacavir succinate GSK HIV infection, AIDS (or Ziagen ®)(reverse transcriptase inhibitor) Reyataz ® Bristol-Myers Squibb HIVinfection, AIDS (atazanavir) Fuzeon Roche/Trimeris HIV infection, AIDS,(Enfuvirtide, T-20) viral fusion inhibitor Trizivir ® HIV infection,AIDS Kaletra ® Abbott HIV infection, AIDS, ARC IMMUNOMODULATORS AS-101Wyeth-Ayerst AIDS Bropirimine Pharmacia Upjohn Advanced AIDS AcemannanCarrington Labs, Inc. AIDS, ARC (Irving, TX) CL246,738 American CyanamidAIDS, Kaposi's sarcoma Lederle Labs EL10 Elan Corp, PLC HIV infection(Gainesville, GA) FP-21399 Fuki ImmunoPharm Blocks HIV fusion with CD4+cells Gamma Interferon Genentech ARC, in combination w/TNF (tumornecrosis factor) Granulocyte Genetics Institute AIDS Macrophage ColonySandoz Stimulating Factor Granulocyte Hoechst-Roussel AIDS MacrophageColony Immunex Stimulating Factor Granulocyte Schering-Plough AIDS,combination Macrophage Colony w/AZT Stimulating Factor HIV Core ParticleRorer Seropositive HIV Immunostimulant IL-2 Cetus AIDS, in combinationInterleukin-2 w/AZT IL-2 Hoffman-LaRoche AIDS, ARC, HIV, inInterleukin-2 Immunex combination w/AZT IL-2 Chiron AIDS, increase inCD4 Interleukin-2 cell counts (aldeslukin) Immune Globulin CutterBiological Pediatric AIDS, in Intravenous (Berkeley, CA) combinationw/AZT (human) IMREG-1 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma,ARC, PGL IMREG-2 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma, ARC,PGL Imuthiol Diethyl Merieux Institute AIDS, ARC Dithio CarbamateAlpha-2 Schering Plough Kaposi's sarcoma Interferon w/AZT, AIDSMethionine- TNI Pharmaceutical AIDS, ARC Enkephalin (Chicago, IL) MTP-PECiba-Geigy Corp. Kaposi's sarcoma AIDS, Muramyl-Tripeptide Amgen incombination w/AZT Granulocyte Colony Stimulating Factor Remune ImmuneResponse Immunotherapeutic Corp. rCD4 Genentech AIDS, ARC RecombinantSoluble Human CD4 rCD4-IgG AIDS, ARC hybrids Recombinant Biogen AIDS,ARC Soluble Human CD4 Interferon Hoffman-La Roche Kaposi's sarcoma, Alfa2a in combination w/AZT AIDS, ARC SK&F106528 Smith Kline HIV infectionSoluble T4 Thymopentin Immunobiology HIV infection Research Institute(Annandale, NJ) Tumor Necrosis Genentech ARC, in combination Factor; TNFw/gamma Interferon ANTI-INFECTIVES Clindamycin with Pharmacia Upjohn PCPPrimaquine Fluconazole Pfizer Cryptococcal meningitis, candidiasisPastille Squibb Corp. Prevention of oral Nystatin Pastille candidiasisOrnidyl Merrell Dow PCP Eflornithine Pentamidine LyphoMed PCP treatmentIsethionate (IM & IV) (Rosemont, IL) Trimethoprim AntibacterialTrimethoprim/sulfa Antibacterial Piritrexim Burroughs Wellcome PCPtreatment Pentamidine Fisons Corporation PCP prophylaxis Isethionate forInhalation Spiramycin Rhone-Poulenc Cryptosporidial diarrheaIntraconazole- Janssen-Pharm. Histoplasmosis; R51211 cryptococcalmeningitis Trimetrexate Warner-Lambert PCP Daunorubicin NeXstar, SequusKaposi's sarcoma Recombinant Human Ortho Pharm. Corp. Severe anemiaassoc. Erythropoietin with AZT therapy Recombinant Human SeronoAIDS-related wasting, Growth Hormone cachexia Megestrol AcetateBristol-Myers Squibb Treatment of anorexia assoc. W/AIDS TestosteroneAlza, Smith Kline AIDS-related wasting Total Enteral Norwich EatonDiarrhea and Nutrition Pharmaceuticals malabsorption related to AIDS

1. A method for treating HIV infection in a human patient comprisingadministering a therapeutically effective amount of1-benzoyl-4-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-piperazine,or a pharmaceutically acceptable salt or solvate thereof, with atherapeutically effective amount of at least one other agent used fortreatment of AIDS or HIV infection selected from the group consisting ofnucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIVreverse transcriptase inhibitors, HIV protease inhibitors, HIV fusioninhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4inhibitors, HIV budding or maturation inhibitors, and HIV integraseinhibitors.
 2. The method of claim 1 wherein the agent is a nucleosideHIV reverse transcriptase inhibitor.
 3. The method of claim 2 whereinthe nucleoside HIV reverse transcriptase inhibitor is selected from thegroup consisting of abacavir, didanosine, emtricitabine, lamivudine,stavudine, tenofovir, zalcitabine, and zidovudine, or a pharmaceuticallyacceptable salt or solvate thereof.
 4. The method of claim 1 wherein theagent is a non-nucleoside HIV reverse transcriptase inhibitor.
 5. Themethod of claim 4 wherein the non-nucleoside HIV reverse transcriptaseinhibitor is selected from the group consisting of delavirdine,efavirenz, and nevirapine, or a pharmaceutically acceptable salt orsolvate thereof.
 6. The method of claim 1 wherein the agent is an HIVprotease inhibitor.
 7. The method of claim 6 wherein the HIV proteaseinhibitor is selected from the group consisting of amprenavir,atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir andfosamprenavir, or a pharmaceutically acceptable salt or solvate thereof.8. The method of claim 1 wherein the agent is an HIV fusion inhibitor.9. The method of claim 8 wherein the HIV fusion inhibitor is enfuvirtideor T-1249, or a pharmaceutically acceptable salt or solvate thereof. 10.The method of claim 1 wherein the agent is an HIV attachment inhibitor.11. The method of claim 1 wherein the agent is a CCR5 inhibitor.
 12. Themethod of claim 11 wherein the CCR5 inhibitor is selected from the groupconsisting of Sch-C, Sch-D, TAK-220, PRO-140, and UK-427,857, or apharmaceutically acceptable salt or solvate thereof.
 13. The method ofclaim 1 wherein the agent is a CXCR4 inhibitor.
 14. The method of claim13 wherein the CXCR4 inhibitor is AMD-3100, or a pharmaceuticallyacceptable salt or solvate thereof.
 15. The method of claim 1 whereinthe agent is an HIV budding or maturation inhibitor.
 16. The method ofclaim 15 wherein the budding or maturation inhibitor is PA-457, or apharmaceutically acceptable salt or solvate thereof.
 17. The method ofclaim 1 wherein the agent is an HIV integrase inhibitor.
 18. The methodof claim 17 wherein the HIV integrase inhibitor is3-[(4-fluorobenzyl)methoxycarbamoyl]-2-hydroxyacrylic acid or2-(2,2)-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(4-fluorobenzyl)-N-methoxyacetamide,or a pharmaceutically acceptable salt or solvate thereof.
 19. Apharmaceutical composition comprising a therapeutically effective amountof1-benzoyl-4-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-piperazine,or a pharmaceutically acceptable salt or solvate thereof, with at leastone other agent used for treatment of AIDS or HIV infection selectedfrom the group consisting of nucleoside HIV reverse transcriptaseinhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIVprotease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors,CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors,and HIV integrase inhibitors, and a pharmaceutically acceptable carrier.20. The composition of claim 19 wherein the agent is a nucleoside HIVreverse transcriptase inhibitor.
 21. The composition of claim 20 whereinthe nucleoside HIV transcriptase inhibitor is selected from the groupconsisting of abacavir, didanosine, emtricitabine, lamivudine,stavudine, tenofovir, zalcitabine, and zidovudine, or a pharmaceuticallyacceptable salt or solvate thereof.
 22. The composition of claim 19wherein the agent is a non-nucleoside HIV reverse transcriptaseinhibitor.
 23. The composition of claim 22 wherein the non-nucleosideHIV reverse transcriptase inhibitor is selected from the groupconsisting of delavirdine, efavirenz, and nevirapine, or apharmaceutically acceptable salt or solvate thereof.
 24. The compositionof claim 19 wherein the agent is an HIV protease inhibitor.
 25. Thecomposition of claim 24 wherein the HIV protease inhibitor is selectedfrom the group consisting of amprenavir, atazanavir, indinavir,lopinavir, nelfinavir, ritonavir, saquinavir and fosamprenavir, or apharmaceutically acceptable salt or solvate thereof.
 26. The compositionof claim 19 wherein the agent is an HIV fusion inhibitor.
 27. Thecomposition of claim 26 wherein the HIV fusion inhibitor is enfuvirtideor T-1249, or a pharmaceutically acceptable salt or solvate thereof. 28.The composition of claim 19 wherein the agent is an HIV attachmentinhibitor.
 29. The composition of claim 19 wherein the agent is a CCR5inhibitor.
 30. The composition of claim 29 wherein the CCR5 inhibitor isselected from the group consisting of Sch-C, Sch-D, TAK-220, PRO-140,and UK-427,857, or a pharmaceutically acceptable salt or solvatethereof.
 31. The composition of claim 19 wherein the agent is a CXCR4inhibitor.
 32. The composition of claim 31 wherein the CXCR4 inhibitoris AMD-3100, or a pharmaceutically acceptable salt or solvate thereof.33. The composition of claim 19 wherein the agent is an HIV budding ormaturation inhibitor.
 34. The composition of claim 33 wherein thebudding or maturation inhibitor is PA-457, or a pharmaceuticallyacceptable salt or solvate thereof.
 35. The composition of claim 19wherein the agent is an HIV integrase inhibitor.
 36. The composition ofclaim 35 wherein the HIV integrase inhibitor is3-[(4-fluorobenzyl)methoxycarbamoyl]-2-hydroxyacrylic acid or2-(2,2)-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(4-fluorobenzyl)-N-methoxyacetamide,or a pharmaceutically acceptable salt or solvate thereof.